Despite the success of new targeted agents and immunotherapies, metastatic melanoma remains an incurable disease for many patients. Although BRAF inhibitors (BRAFi) show promise for reducing metastatic burden, some melanomas are intrinsically resistant, and most responding patients eventually acquire resistance. These data underline the importance of identifying new markers for treatment response and novel drug combinations for treating metastatic and BRAFi-resistant disease. We show that Abl/Arg non-receptor tyrosine kinases are highly expressed in melanoma, and are activated in a subset (40-60%). Moreover, SFKs and BRAFV600E, the most common genetic alteration in melanoma, both contribute to Abl/Arg activation in melanoma cells. Once activated, Abl/Arg promote proliferation, survival, a switch in EMT transcription factor expression, invasion, and metastasis and bidirectionally regulate and potentiate BRAFV600E signaling. Moreover, inhibitors of Abl/Arg and a parallel pathway, which drives intrinsic BRAFi resistance (PI3K/Akt/PTEN), cooperate to prevent melanoma viability and tumor growth. Based on these findings, we hypothesize that BRAFV600E/ERK and SFKs cooperatively activate Abl/Arg, which synergize with Akt to drive melanoma development, progression, phenotypic switching and subsequent resistance. We propose a comprehensive hypothesis-driven experimental design that will establish Abl/Arg as novel and exploitable drug targets. Aim 1 will define the mechanism by which Abl/Arg are activated in melanoma. To achieve our objective, biochemical, molecular biological and cell biological approaches using melanocytes, melanoma cell lines, tissue microarrays, pharmacological inhibitors/RNAi, mass spectrometry, and immunohistochemistry will be used to test the prediction that BRAFV600E/ERK-mediated phosphorylation prevents nuclear targeting of Abl and facilitates activation of Abl/Arg by SFKs. In Aim 2, 2D/3D culture, rescue experiments and xenograft approaches will be used to identify the mechanism by which Abl/Arg drive the EMT transcription factor switch, potentiate BRAFV600E signaling, and promote acquired BRAFi resistance. Finally, in Aim 3, genetically engineered (GEM) and xenograft mouse models as well as loss- and gain-of-function approaches will be used to test the prediction that Abl/Arg cooperate with activated Akt, in mutant PTEN melanomas, to promote melanoma growth/metastasis and BRAFi/MEKi resistance. Data obtained from this project not only will allow us to gain important insight into fundamental mechanisms by which Abl/Arg are activated in melanoma, which likely is applicable to other solid tumors, but also may lead to clinical studies testing the efficacy of Akt inhibitors in combination with Abl/Arg inhibitors for treating mutant BRAF/PTEN melanomas, which often are resistant to current therapeutic approaches.